The basis of learning and memory is likely to depend on hebbian mechanisms of associativity as well as homeostatic mechanisms that maintain cell stability, both acting on many of the same substrates. alphaCaMKII, a molecule that has been shown to regulate the threshold for induction of LTP and mediate trafficking of AMPA receptors, is perhaps involved in both such mechanisms. alphaCaMKII is known to exist as a holoenzyme along with a second isoform, betaCaMKII, in a heteromeric configuration. Interestingly, while both isoforms have the ability to decode calcium signals, they differ significantly in their calmodulin affinities optimizing the isoform for decoding higher Ca2+ frequencies. An examination of the effect of activity on the regulation of alpha and betaCaMKII in hippocampal neurons showed that they are reciprocally regulated in response to changes in activity such that the ratio favors a during increased activity, perhaps tuning the cell to higher frequency signals. Moreover, beta CaMKII was found to regulate alpha suggesting that their reciprocity of expression is tightly coupled. Based on this data we hypothesize that the reciprocal regulation of alpha and betaCaMKII in response to activity may be a homeostatic mechanism that maintains response stability by regulating synaptic input. This study will further examine the regulation of alpha and betaCaMKII in different regions of the brain, explore the functional consequences of this regulation on synaptic plasticity using electrophysiology and examine the downstream signaling associated with their regulation using cDNA microarrays. This work relates to how the cell processes information and is likely to be important in understanding learning and memory as well as diseases such as epilepsy that result from network destabilization. These links are strongly supported by evidence from CaMKII loss of function phenotypes showing impairment in spatial memory (alphaCaMKll KO mouse) as well as increased incidence of seizure (alphaCaMKII KO mouse and C. elegans CAMKII 1f mutant)